Asthma is a disease characterized by reversible airflow obstruction and bronchial inflammation. The goal of this proposal is to understand how environmental antigens influence local immunologic processes in the lung and airways and result in the inflammatory infiltrate and bronchial hyperresponsiveness seen in this disease. There is considerable recent evidence that CD4+ T lymphocytes (Th2 cells) that secrete interleukin-4 and interleukin-5 are involved in the pathogenesis of asthma. These cytokines are associated with airway eosinophilia and high IgE levels that are typically seen in atopic asthmatics. We plan to study airway inflammation and bronchial hyperresponsiveness in the mouse by investigating the role of inhaled antigens in the induction of pulmonary Th2 cells. The induction of Th2 cells during an immune response has been shown to be influenced by three factors: the antigen itself, the type of antigen presenting cell that interacts with the T cell, and the cytokines present at the site of CD4 T cell stimulation. We will use three groups of transgenic mice which will allow us to investigate how each of these factors individually effects Th2 cell induction in the lung and airways. Once we have established conditions that control Th2 dominant responses in the lung, we will examine pulmonary histopathology and measure airway resistance in provoked mice. Thus, we will test our hypothesis that airway hyperresponsiveness and inflammation are associated with selective pulmonary Th2 lymphocyte activation. Further, we will investigate methods to abrogate Th2 responses once they are established. From these studies we hope to gain insight into how the immunologic responses associated with asthma can be manipulated. Overall, we hope to shed light on the complex immunopathogenesis of airway inflammation and its association with bronchial hyperresponsiveness in a transgenic mouse model.